The present invention relates to wrinkling modifiers and anti-aging cosmetic compositions, and more particularly to anti-aging cosmetic compositions which are excellent in the effects of suppressing wrinkling and of removing or smoothing wrinkles.
It is a significant concern of, particularly, women to maintain the healthy and beautiful skin. However, the condition of the skin is always affected by factors such as humidity, ultraviolet rays, cosmetic compositions, aging, diseases, stress and eating habits. As the result thereof, various skin troubles such as the decrement of various functions of the skin and the aging of the skin occur. Of these, wrinkles occur due to dermal aging by aging, light aging by exposure to sunbeam, or the like. More specifically, cells f or producing fibers of the dermis are made small and lessened by exposure to sunbeam or with the increase in age. In particular, collagen fibers are lost to a great extent, and so the skin is aged by degeneration of the dermis, reduction of subcutaneous adipose tissue and the like, which forms the cause of wrinkling, relaxation, and loss of resilience.
Various compositions and methods have heretofore been proposed for preventing or treating the aging effects such as wrinkling [Japanese Patent Application Laid-Open Nos. 185005/1987, 502546/1987, 72157/1990, 288822/1990 and 41419/1995, Japanese Patent Application Laid-Open (KOHYO) No. 510542/1994 (through PCT route), etc.]. However, all of these proposals have not been fully satisfactory in the effect of modifying wrinkling (or preventing wrinkling and removing wrinkles). There has thus been a demand for development of cosmetic skin care compositions excellent in the effect of modifying wrinkling.
It is an object of the present invention to provide wrinkling modifiers and anti-aging cosmetic compositions which can solve the above-described problems, are excellent in the effects of suppressing wrinkling without impairing normal dermatophysiology and removing wrinkles, and give users a pleasant feeling upon use.
In view of the foregoing circumstances, the present inventors have carried out an extensive investigation with a view toward achieving the above object. As a result, it has been found that guanidine derivatives having a specific structure or acid-addition salts thereof are excellent in the effect of modifying wrinkling and give users a pleasant feeling upon use, thus leading to completion of the present invention.
According to the present invention, there are thus provided a wrinkling modifier and an anti-aging cosmetic composition, each comprising a guanidine derivative represented by the following general formula (1): 
wherein 
is a heterocyclic group selected from azetidine, pyrrolidine, piperidine, piperazine or morpholine, and R1 and R2 are the same or different from each other and independently a hydrogen atom, or an alkyl, hydroxyl, hydroxyalkyl, carboxyl, carboxyalkyl or amidino group, or a salt thereof.
According to the present invention, there is also provided a cosmetic skin care composition comprising the wrinkling modifier (1) and a synthetic sphingosine derivative represented by the following general formula (2): 
wherein R3 is a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 40 carbon atoms, R4, R5, R6, R7 and R8 are independently a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, which may be substituted by at least one hydroxyl group, and X and Y are independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, which may contain at least one oxygen atom in its structure.
Among the heterocyclic groups represented by 
in the general formula (1) which represents the guanidine derivatives or the salts thereof used in the present invention, pyrrolidine, piperidine, piperazine and morpholine are preferred. The alkyl groups represented by R1 and R2 include linear or branched alkyl groups having 1 to 6 carbon atoms. Of these, alkyl groups having 1 to 4 carbon atoms are preferred. Specific examples of the alkyl groups include methyl, ethyl, n-propyl and isopropyl groups. Of these, methyl group is particularly preferred. The hydroxyalkyl groups include hydroxyalkyl groups having 1 to 6 carbon atoms, and hydroxyalkyl groups having 1 to 4 carbon atoms are preferred. Specific examples of the hydroxyalkyl groups include hydroxymethyl, hydroxyethyl and hydroxypropyl groups, with the hydroxymethyl and hydroxyethyl groups being particularly preferred. The carboxyalkyl groups include carboxyalkyl groups having 2 to 7 carbon atoms, and carboxyalkyl groups having 2 to 5 carbon atoms are preferred. Specific examples of the carboxyalkyl groups include carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl groups, with the carboxymethyl and carboxyethyl groups being particularly preferred.
R1 and R2 may be the same or different from each other and be an optional combination of 2 groups.
Stereoisomers exist in the guanidine derivatives (1) because of the presence of asymmetric carbon atoms. In the present invention, all these stereoisomers and mixtures thereof may be used.
Specific examples of the guanidine derivatives (1) include N-amidinoproline, 2-hydroxymethyl-1-pyrrolidine-carboxamidine, 3-hydroxy-1-pyrrolidinecarboxamidine, N-amidinoaziridine-2-carboxylic acid, N-amidino-2-piperidinecarboxylic acid, N-amidino-3-piperidine-carboxylic acid, N-amidino-4-piperidinecarboxylic acid, N-amidino-4-piperidinepropionic acid, pyrrolidine-carboxamidine, piperidinecarboxamidine, 2-methyl-piperidinecarboxamidine, 3-methylpiperidinecarboxamidine, 4-methylpiperidinecarboxamidine, 2-methylmorpholine-carboxamidine, 3-methylmorpholinecarboxamidine, N-methyl-piperazinecarboxamidine, N-2-hydroxyethylpiperazine-carboxamidine and piperazinecarboxamidine.
An acid for forming salts of the guanidine derivatives (1) may be either an organic acid or an inorganic acid. Examples thereof include monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, phenylacetic acid, cinnamic acid, benzoic acid, sorbic acid, nicotinic acid, urocanic acid and pyrrolidone-carboxylic acid; dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, pimelic acid, cork acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, phthalic acid and terephthalic acid; hydroxy acids such as glycolic acid, lactic acid, malic acid, tartaric acid, citric acid and o-, m- or p-hydroxybenzoic acid; amino acids such as glycine, alanine, xcex2-alanine, valine, leucine, phenylalanine, tyrosine, serine, threonine, methionine, cysteine, cystine, proline, hydroxyproline, pipecolic acid, triptophan, aspartic acid, asparagin, glutamic acid, glutamine, lysine, histidine, ornithine, arginine and aminobenzoic acid; lower alkyl-sulfonic acids such as methanesulfonic acid and trifluoro-methanesulfonic acid; arylsulfonic acids such as benzene-sulfonic acid and p-toluenesulfonic acid; hydrohalogenic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydriodic acid; and inorganic acids such as perchloric acid, sulfuric acid, nitric acacia, phosphoric acid and carbonic acid.
The guanidine derivatives (1) or the salts thereof can be obtained in accordance with, for example, a preparation process represented by the following reaction scheme: 
wherein 
R1 and R2 have the same meanings defined above.
More specifically, a cyclic amine derivative (3) is reacted with a guanidylating reagent, whereby a guanidine derivative (1) or a salt thereof can be obtained.
Examples of the guanidylating reagent include known guanidylating reagents such as cyanamides, S-alkyl-isothioureas, O-alkylisoureas, aminoiminomethanesulfonic acid, 3,5-dimethyl-1-guanylpyrazole, 1H-pyrazole-1-carbamidine.
In the case where an S-alkylisothiourea, O-alkyl-isourea, 3,5-dimethyl-1-guanylpyrazole or 1H-pyrazole-1-carbamidine is used, the reaction may be conducted by stirring the reactants at 0 to 200xc2x0 C. for 1 to 72 hours in the presence or absence of a base such as barium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen-carbonate, sodium carbonate, aqueous ammonia, a tertiary amine such as triethylamine, N,N-dimethylaniline, N,Nxe2x80x2-dimethylpiperazine or N-methylpiperidine, or pyridine. In the case where a cyanamide is used, it is only necessary to stir the reactants at 0 to 200xc2x0 C. for 1 to 72 hours, or stir the reactants at 25 to 200xc2x0 C. for 1 to 72 hours in the presence of any one of the acids exemplified for the formation of the salts of the guanidine derivatives.
After completion of the reaction, as needed, the acid may be added to the reaction product in accordance with a method known per se in the art to isolate it as an acid-addition salt.
The guanidine derivatives (1) or the salts thereof may be used either singly or in any combination thereof. The amount of such a compound incorporated in the wrinkling modifiers and the cosmetic compositions is preferably 0.001 to 50% by weight. It is particularly preferred that it be incorporated in an amount of 0.001 to 30% by weight, more preferably 0.01 to 20% by weight, since the feeling upon use is improved, to say nothing of the wrinkling-modifying effect.
The synthetic sphingosine derivative is represented by the formula (2). Examples of the linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 40 carbon atoms represented by R3 in the general formula (2) include alkyl groups such as n-butyl, sec-butyl, pentyl, hexyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, 5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl, 2-heptylundecyl and methyl-branched isostearyl groups; alkenyl groups such as butenyl, hexenyl, oleyl, 9-octadecenyl, 9,12-octadeca-dienyl, 3,7-dimethylocta-2,6-dienyl and 3,7,11-trimethyl-2,6,10-dodecatrienyl groups; cycloalkyl groups such as cyclopentyl and cyclohexyl groups; and aryl groups such as phenyl, tolyl and naphthyl groups.
In the present invention, the linear or branched, saturated hydrocarbon groups having 4 to 40 carbon atoms are preferred. Of these, tetradecyl, octadecyl and methyl-branched isostearyl groups are particularly preferred.
The hydrocarbon groups having 1 to 10 carbon atoms represented by R4 to R8, which may be substituted by at least one hydroxyl group, include alkyl groups and mono-,di- or tri-hydroxyalkyl groups such as methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, hydroxyethyl, 2-hydroxy-ethyl and 3,3,3-trihydroxypropyl groups. However, a hydrogen atom or methyl group is preferred as each of R4 to R8.
Examples of the alkyl groups having 1 to 6 carbon atoms represented by X and Y, which may contain at least one oxygen atom in their structures, include glucosyl, fructosyl, galactosyl, mannosyl, methyl, ethyl, propyl, hexyl, 2-hydroxyethyl, 3-hydroxyethyl, 4-hydroxypropyl, 5-hydroxy-6-hydroxybutyl, 2,3-dihydroxypropyl, 2-(1,2,3-trihydroxypropyl)methyl and 3-(2,3-dihydroxypropyloxy)-2-hydroxyethyl groups. However, a hydrogen atom or 2-hydroxyethyl group is particularly preferred as each of X and Y.
These sphingosine derivatives may be used either singly or in any combination thereof. The amount of such a derivative incorporated in the cosmetic compositions is preferably 0.0001 to 10% by weight. It is particularly preferred that it be incorporated in an amount of 0.001 to 2% by weight, since the feeling upon use is improved, to say nothing of the wrinkling-modifying effect.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated an organic acid, an inorganic acid such as phosphoric acid, sulfuric acid or hydrochloric acid, or an ester thereof. The incorporation of such a compound is preferred because the wrinkling-modifying effect can be more enhanced.
No particular limitation is imposed on the organic acid or the ester thereof so far as it is not included in the guanidine derivatives (1). For example, xcex1- or xcex2-hydroxycarboxylic acids, dicarboxylic acids, fatty acids and esters thereof may be mentioned. One or more of these compounds may be incorporated. Examples of these organic acids include those represented by the following formulae (4) to (6), and esters thereof. 
In the formula (4), Y1 is a hydrogen atom or CH3(C1Hm)n (l being an integer of 1 to 27, m being an integer of 2 to 54, and n being 0 or 1). In the formula (5), R9 and R10 are independently a hydrogen atom, a saturated or unsaturated, branched, linear or cyclic alkyl group having 1 to 25 carbon atoms, an aralkyl group or an aryl group, q is an integer of 1 to 9, and r is an integer of 0 to 23. In the formula (6), s is an integer of 0 to 9, and t is an integer of 0 to 23. More specific examples of the organic acids include ascorbic acid, xcex5-aminocaproic acid, erythorbic acid, citric acid, succinic acid, tartaric acid, sorbic acid, dehydroacetic acid, lactic acid, urocanic acid, edetic acid, hydroxybenzonesulfonic acid, orotic acid, capric acid, glycolic acid, cerotic acid, nicotinic acid, hydroxyethanediphosphonic acid, phytic acid, fumaric acid, malic acid, levulinic acid, acrylic acid and oligomers or polymers thereof, and esters thereof.
Examples of the fatty acids include linolic acid, xcex3-linolenic acid, columbinic acid, icosa-(xcex7-6,9,13)-trienoic acid, arachidonic acid, xcex1-linolenic acid, thymunodonic acid, hexanoic acid, isostearic acid, undecylenic acid, stearic acid, palmitic acid, behenic acid, myristic acid, coconut oil fatty acid, lauric acid, lanolinic acid and DHA, and besides hydroxy fatty acids such as 12-hydroxystearic acid. The inorganic acids or the esters thereof include monoalkylphosphoric acids such as cetylphosphoric acid, and dialkylphosphoric acids.
In the present invention, among these organic acids and inorganic acids, the organic acids represented by the formulae (4), (5) and (6) are preferred. The dicarboxylic acids represented by the formula (6) are more preferred, with succinic acid being particularly preferred because the wrinkling-modifying effect can be more enhanced. The organic acid, inorganic acids and the like may be used either singly or in any combination thereof. The amount of such an acid incorporated in the wrinkling modifiers and the cosmetic compositions is preferably 0.001 to 30% by weight. It is particularly preferred that it be incorporated in an amount of 0.005 to 20% by weight, more preferably 0.01 to 10% by weight, since the feeling upon use is improved, to say nothing of the wrinkling-modifying effect. An incorporating ratio of the organic acid, inorganic acid or the like to the guanidine derivative or the acid-addition salt thereof is preferably 0.5:99.5 to 99.5:0.5 in terms of weight ratio. It is particularly preferred that the ratio be 5:95 to 95:5, since the wrinkling-modifying effect can be more enhanced.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated an oily substance. No particular limitation is imposed on the oily substance, and examples thereof include hydrocarbons such as solid and liquid paraffins, crystal oil, ceresin, ozocerite, montan wax, squalane and squalene; ester oils such as olive oil, carnauba wax, lanolin, jojoba oil, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, isopropyl stearate, neopentylglycol dicaprate and glycerol isostearate; higher alcohol such as cetanol and stearyl alcohol; and naturally extracted sphingosine derivatives and synthetic ceramide derivatives represented by the following general formula (7): 
wherein R11 is a linear or branched, saturated or unsaturated hydrocarbon group having 10 to 26 carbon atoms, R12 is a linear or branched, saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms, and A and B are independently a hydrogen atom or a sugar residue. One or more of these oily substances may be used.
When these oily substances are incorporated, they are preferably incorporated in a proportion of 0.001 to 50% by weight, particularly preferably 0.005 to 30% by weight into the wrinkling modifiers and the cosmetic compositions.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated a sterol. Examples of the sterol include cholesterol, provitamin D3, campesterol, stegmastanol, stegmasterol, 5-dihydrocholesterol, xcex1-spinasterol, palysterol, clionasterol, xcex3-sitosterol, stegmastenol, sargasterol, apenasterol, ergostanol, sitosterol, colubisterol, chondrillasterol, polyphellasterol, haliclonasterol, neospongosterol, fucosterol, aptostanol, ergostadienol, ergosterol, 22-dihydroergosterol, brassicasterol, 24-methylene-cholesterol, 5-dihydroergosterol, dehydroergosterol, fungisterol, cholestenol, coprostenol, zymosterol, 7-hetocholesterol, lathosterol, 22-dehydrocholesterol, xcex2-sitosterol, cholestatrien-3xcex2-ol, coprostanol, cholestanol, ergostenol, 7-dehydrocholesterol, 24-dehydrocholestadion-3xcex2-ol, equilenine, equilin, estrone, 17xcex2-estradiol, androst-4-ene-3 xcex2,17xcex2-diol and dehydroepiandrosterone. One or more of these sterols may be used.
When these sterols are incorporated, they are preferably incorporated in a proportion of 0.001 to 50% by weight, particularly preferably 0.005 to 30% by weight into the cosmetic skin care compositions.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated a surfactant. Examples of the surfactant include polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, glycerol fatty acid esters, polyoxyethylene hardened castor oil alkylsulfates, polyoxyethylene alkylsulfates, alkylphosphates, polyoxyethylene alkylphosphates, alkali metal salts of fatty acids, sorbitan fatty acid esters, glycerol fatty acid esters and alkyl glyceryl ethers. One or more of these surfactants may be used.
When these surfactants are incorporated, they are preferably incorporated in a proportion of 0.001 to 50% by weight, particularly preferably 0.005 to 30% by weight into the wrinkling modifiers and the cosmetic compositions.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated a water-soluble polyhydric alcohol. Examples of the water-soluble polyhydric alcohol include alcohols having two or more hydroxyl groups in their molecules, for example, ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, glycerol and polyglycerols such as diglycerol, triglycerol and tetraglycerol, glucose, maltose, maltitol, sucrose, fructose, xylitol, sorbitol, maltotriose, threitol, erythritol, and alcohols obtained by reduction of amylolytic sugar. One or more of these alcohols may be used.
When these water-soluble polyhydric alcohols are incorporated, their proportion in the wrinkling modifiers and the cosmetic compositions may be suitably determined according to the preparation forms of the modifiers and the cosmetic compositions. However, it is generally preferred to incorporate them in a proportion of 0.001 to 75% by weight, particularly preferably 0.1 to 25% by weight.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated powder. Examples of the powder include extenders such as mica, talc, sericite, kaolin, nylon powder and polymethylsil sesquioxane; inorganic pigments such as pearl; organic pigments such as Red Color No. 202, Red Color No. 226, Yellow Color No. 4 and aluminum lake; and inorganic powders for ultraviolet screening, such as zinc oxide, titanium oxide, zirconium oxide and iron oxide. These powders may be subjected to a silicone treatment with methyl hydrogenmethylpolysiloxane, trimethylsiloxysilicic acid, methylpolysiloxane or the like, a fluorine treatment with a perfluoroalkyl phosphate, perfluoroalcohol or the like, an amino acid treatment with N-acylglutamic acid or the like, a lecithin treatment, a metal soap treatment, a fatty acid treatment, an alkylphosphate treatment, or the like before their use.
When these powders are incorporated, their proportion in the wrinkling modifiers and cosmetic compositions may be suitably determined according to the preparation forms of the modifiers and the cosmetic compositions. However, it is generally preferred to incorporate them in a proportion of 0.001 to 50% by weight, particularly preferably 0.005 to 30% by weight.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, may be further incorporated a silicone. No particular limitation is imposed on the silicone so far as it is that commonly incorporated into the classical cosmetic compositions. Examples thereof include octamethylpolysiloxane, tetradecamethylpolysiloxane, methylpolysiloxane, high-polymeric methylpolysiloxane and methylphenylpolysiloxane, and besides methylpolycyclosiloxanes such as octamethylcyclotetrasiloxane and decamethylcyclopenta-siloxane, trimethylsiloxysilicic acid, and modified silicones such as polyether alkyl-modified silicone and alkyl glyceryl ether-modified silicone.
When these silicones are incorporated, their proportion in the wrinkling modifiers and the cosmetic compositions may be suitably determined according to the preparation forms of the modifiers and the cosmetic compositions. However, it is generally preferred to incorporate them in a proportion of 0.001 to 50% by weight, particularly preferably 0.005 to 30% by weight.
Into the wrinkling modifiers and the cosmetic compositions according to the present invention, various ingredients commonly incorporated into the classical cosmetics, quasi-drugs, drugs and the like may be incorporated so far as no detrimental influence is thereby imposed on the objects of the present invention. Examples of such ingredients include inorganic salts such as magnesium sulfate, potassium sulfate, sodium sulfate, magnesium chloride and sodium chloride; viscosity modifiers such as polyvinyl alcohol, carboxyvinyl polymers, carboxymethyl cellulose, gelatin, tragacanth gum, xanthan gum, hyaluronic acid, tuberose extract, agarose and sodium alginate; and besides antiseptics such as parabens, pH adjusters, wetting agents, ultraviolet absorbents, coloring matter, medicinally-effective ingredients and perfume bases.
The wrinkling modifiers and the cosmetic compositions according to the present invention are preferably at a pH of 2 to 11. It is particularly preferred that the pH be at 3 to 10, since the normal physiological function of the skin can be retained. The wrinkling modifiers and the cosmetic compositions according to the present invention can be prepared in accordance with a method known per se in the art, formulated into any desired forms such as emulsions, dispersions, two-layer compositions, solutions and gel, and provided as toilet waters, milky lotions, creams, packs, paps, foundations and the like.